Ophthalmic preparations are administered into the eye for treating a wide variety of ocular disorders. Usually, these preparations are sterile products designed for either topical application onto the internal eyelid or instillation into the cul-de-sacs strategically positioned between the eyeball (cornea and bulba conjunctive) and eyelides (palpebral conjunctiva). Ophthalmic preparations may also be prepared in the form of an injection. At the present time, the following are the most common methods of delivering therapeutic substance to the eye: by the mechanism of some sort of vehicle or delivery system to the surface of the eye comprising ocular solutions, suspensions, ointments, gels and inserts; and by either periocular or systemic injections. If there are any diseases within the eye to be treated pharmaceutically, however, the obviously safe and most preferred method of providing that treatment would be by extraocular topical application. Some ophthalmic disorders require the replacement or augmentation of the tear film layer which may be deficient either quantitatively or qualitatively. A topical agent which would provide lubrication and protection to the external surfaces of the eye is required in these disorders. Such disorders include dry eyes syndrome caused by keratoconjunctivitis sica, tear abornalities, atrophy of the lacrimal gland, ocular pemphigoid, chemical burns, chronic keratoconjunctivitis, corneal epithelium diseases (corneal ulcers, recurrent corneal erosion and marginal ulcers), and corneal vascularization due to corneal injury, infection or transplantation.
Notwithstanding the safety and apparent convenience of topical ophthalmic preparations, several have significant disadvantages which adversely affect their efficiency and efficacy. Some of the disadvantages are inadequate persistence or retention in the cul-de-sacs, irritation, burning or stinging sensations, stickiness, and discomfort, all of which can be attributed to the vehicle, preservatives or drug itself. Because of these disadvantages, patients may not even comply with their doctor's advice for using them.
Presently, all ophthalmic preparations, including those commonly referred to as "eye drops", are required to be sterile before their instillation into the eye. In most ophthalmic preparations, sterility is achieved or maintained by incorporating preservatives. Some preservatives, however, are known to adversely affect the surface structure of the corneal epithelium and disrupt the microvilli which are necessary for the cornea to retain the tear film layer. Thus, the mucin layer of the tear film cannot be properly adsorbed onto the abnormal microvilli of the corneal and conjunctiva surfaces. Without adsorption of the mucin layer onto the corneal and conjunctiva surfaces, the wetting of these surfaces by aqueous tear film layer is hindered. Accordingly, irritation and discomfort result.
In addition to the sterility requirement, eye drops, comprising suspensions and solutions, are rapidly eliminated from the cul-de-sacs by the naso-lacrimal drainage system. As a result of their aqueous properties and low specific gravity, drops are miscible with the secretory liquids of the eye subjecting them to a faster rate of expulsion by way of the blinking mechanism. Unfortunately, their presistence in the cul-de-sacs is limited thereby significantly comprising efficiency and efficacy. Thus, to achieve therapeutic results, opthalmic eye drops require frequent administration. Because of the physical properties of suspensions, they tend to remain longer in the cul-de-sacs than solutions. Nevertheless, particles are dispersed throughout suspensions which can be irritating to the corneal and conjunctiva surfaces and frequent administration is still required.
Ophthalmic ointments and gels also cause undesirable effects when applied to the internal eyelid. Upon application, they produce a film over the corneal and conjunctiva surfaces blurring vision while usually failing to deliver a uniform dose. Moreover, they may interfere with the preocular tear film precluding its attachment to the corneal and conjunctiva surfaces. Periocular and systemic injections require an ophthalmologist not only to administer but to monitor the drug. Injections tend to cause the patient a great deal of pain and discomfort, anxiety, and inconvenience. Eye inserts provide a delivery system that maintains a low but uniform and constant delivery of a drug. Since the drug is delivered for the duration, frequent administration, as with drops, is not necessary. The major disadvantages associated with ocular inserts involve unnoticed loss of the insert from the eye, slippage of the insert into the area of sight, rupturing of the insert's membrane subjecting the delicate structures of the eye to excessive medication, possible tachyphylaxis, and structural changes in the ciliary muscle resulting from the constant exposure to the drug. Furthermore, there is some degree of manual dexterity required of the patient to position the insert therapeutically and strategically correct.
In contact lens wear, injury to the corneal epithelium may evolve as a direct consequence from the juxtaposition of the contact lens with the corneal surface. Because contact lens are required to be durable and transparent, the materials presently available for their manufacture are somewhat impermeable to oxygen and carbon dioxide as well as other small molecules. The problems observed with contact lens manufactured from these materials relates to recurrent corneal edema secondary to suboxidation of the corneal epithelium. That is, when a contact lens is positioned over the cornea, insufficient oxygen will diffuse through it, thereby irritating as well as precluding normal gaseous exchanges of the cornea. The net effect is to cause suboxidation, edema, and irritation resulting in superficial vascularization, and possible opacification of the cornea.
With respect to corneal epithelial disease, e.g., corneal ulcers and marginal corneal ulcers, there is a breakdown of the epithelial barrier which may result in infectious diseases and chronic recurrent breakdowns. The cornea, due to these disorders, will increase in hydration and loss of transparency. Thus, there is a need for proper ophthalmic preparations that can promote rapid and proper healing of such diseases to avoid formation of corneal scars or opacities. Corneal transplantation or repair is indicated when the cornea has become opaque, infiltrated, or diseased. Because the healing process, as stated above, results in corneal opacification and scars, normal vision can be partially or totally obstructed. In general, corneal transplantation or repair increases hydration while decreasing oxygenation of the cornea. Thus, an ingrowth of vessels is sometimes seen within the cornea after repair or transplantation responding to the corneal scar tissue, increase in hydration and lack of oxygen. Unfortunately, corneal repair or transplantation, as with corneal epithelial disorders, can occlude normal vision when corneal vascularization results.
It is apparent from the above brief overview of various ophthalmic preparations for the eye in pathological processes and the current state of knowledge that there are vital needs for more effective, efficacious and advantageous extraocular ophthalmic preparations.